Ruthenium-catalyzed synthesis of biaryl compounds in water

ABSTRACT

Using a [RuCl2(arene)]2 complex and a formate source, a directed ortho C—H insertion and aryl-aryl coupling sequence in water provides biaryl compounds useful in the preparation of biologically active molecules and intermediates. Reactions may be conducted in the ambient atmosphere. Ruthenium catalysts prepared from [RuCl2(arene)]2 and a formate source may be prepared in situ or isolated for later use.

REFERENCE TO EARLIER FILED APPLICATIONS

This application is a 371 national phase of PCT/US2014/059281, filedOct. 6, 2014, and claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 61/961,224, filed Oct. 8, 2013, thedisclosures of which are incorporated, in their entirety, by thisreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel ruthenium catalysts and their usefor performing carbon-carbon bond formation in aqueous media to produceuseful biaryl compounds.

2. Description of the Related Art

Synthesis of biaryl moieties are of special interest as they arecommonly found in many organic compounds including oils, drugs, flavors,petrochemicals, fragrances and food. For example, biphenyl moietiesappear in many drug molecules such as losartan, valsartan, azilsartan,and anacetrapib, among others. Biaryls even appear in the liquid crystalmixture of commercial liquid crystal displays (LCD) as cyano-substitutedbiphenyl molecules containing long aliphatic tails. Biaryl moities arefound in intermediate structures during the production of emulsifiers,optical brighteners, crop production products, and plastics. Substitutedbiphenyl structures are repeatedly found in natural products such asalkaloids and appear in numerous biologically active agents inpharmaceutical and agrochemical specialties. Polyaromatic compoundscontaining multiple aryl-aryl bonds possess original physicalproperties, which could lead to applications as organic conductors orsemiconductors. Di- or tri-aromatic rings are also the backbone ofligands used for asymmetric catalysis.

Biaryl compounds are commonly prepared using well-known reactions suchas the Suzuki and Stille couplings. These processes require one of thereaction partners to have either a boron or tin-bearing carbon,respectively, at the carbon where bond formation takes place.Alternatively, biaryl bonds may be formed using transitionmetal-catalyzed directed ortho functionalization and coupling. Thisprocess employs an aryl reactant bearing a substituent capable ofdirecting transition metal insertion at the ortho position, therebyallowing bond formation between the site of metal insertion and a carbonatom on a reaction partner substituted with a suitable leaving group(e.g., a halide). Ortho DG's (Directing Groups) are strong coordinatingor chelating groups that have the effect of increasing the kineticacidity of protons in the ortho-position.

Typically, transition metal-catalyzed ortho C—H functionalization andcoupling are achieved in N-methylpyrrolidinone (NMP), dimethylformamide(DMF), dimethylacetamide (DMAc), or similar solvents. These solvents areundesirable because of their toxicity and/or high boiling points. Also,coupling reactions with transition metals are often carried out underinert atmosphere, such as with a Schlenk tube, due to sensitivity of thecatalyst to the ambient atmosphere. Thus, because of disposal andtoxicity issues, and general ease in handling and manipulation, there isan interest in finding more environmentally friendly processes forforming biaryl bonds by transition metal-catalyzed ortho C—Hfunctionalization and coupling.

SUMMARY OF THE INVENTION

The present invention relates to novel ortho directing groups, rutheniumcatalysts and methods for effecting ortho C—H metalation and coupling inaqueous media to form useful biaryl compounds. In a first aspect of theinvention, a first aryl compound is reacted with a second aryl compoundin water in the presence of a catalytically effective amount of a[RuCl₂(arene)]₂ complex and a source of formate. The first aryl compoundincludes first and second ring atoms where the second ring atom isappended with a directing group and the first ring atom is located inthe ortho position with respect to the second ring atom and is the siteof reaction with the second aryl compound. In turn, the second arylcompound includes a first ring atom that is substituted with a leavinggroup. The reaction between the first aryl compound and the second arylcompound results in the formation of a carbon-carbon bond between thefirst ring atom of the first aryl compound and the first ring atom ofthe second aryl compound.

A second aspect of the invention provides ruthenium catalysts preparedby the reaction of a [RuCl₂(arene)]₂ complex with a source of formate.The ruthenium catalysts may be prepared in situ or isolated and may beused to prepare useful biaryl compounds.

A third aspect of the invention provides a new ortho directing group offormula

protected derivatives thereof, and methods of use thereof to prepareuseful biaryl compounds.

DETAILED DESCRIPTION 1. Definitions

The term “aryl” as used herein, refers to a carbocyclic aryl or aheteroaryl as those terms are defined herein.

The terms “biaryl” or “biaryl compound” as used herein, refer tomolecules containing two aryl rings connected by a carbon-carbon singlebond. The individual aryl rings may be either carbocyclic aryl orheteroaryl.

The term “alkyl” as used herein, means a straight or branched chainsaturated hydrocarbon. Representative examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon and containing at least one carbon-carbon double bond.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkynyl,” as used herein, means a straight or branched chainhydrocarbon and containing at least one carbon-carbon triple bond.Representative examples include propynyl, butynyl, pentynyl, and thelike.

The term “alkylene,” as used herein, means a divalent group derived froma straight or branched chain hydrocarbon. Representative examples ofalkylene include, but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and —CH₂CH(CH₃)CH(CH₃)CH₂—.

The term “alkenylene,” as used herein, means a divalent group derivedfrom a straight or branched chain hydrocarbon and containing at leastone carbon-carbon double bond. Representative examples of alkenyleneinclude, but are not limited to —CH═CH—, —CH₂CH═CH—, and—CH₂CH═CH(CH₃)—.

The term “alkynylene,” as used herein, means a divalent group derivedfrom a straight or branched chain hydrocarbon and containing at leastone carbon-carbon triple bond. Representative examples of alkynyleneinclude, but are not limited to —CH₂—C≡C—, —CH₂CH₂—C≡C—, and—C≡C—CH₂CH(CH₃)CH₂—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, and hexyloxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup of 1 to 4 carbons. Representative examples of alkoxyalkyl include,but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, etc.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through a C(O)group.

The terms “haloalkyl,” “haloalkenyl,” and “haloalkynyl” as used herein,mean, respectively an alkyl, alkenyl, or alkynyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. For example, representative examples ofhaloalkyl include, but are not limited to, 2-fluoroethyl,2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trifluoro-1,1-dimethylethyl, and the like.

The term “haloalkoxy,” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five, or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkoxy include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, andpentafluoroethoxy.

The term “haloalkoxyalkyl” as used herein, means a haloalkoxy group, asdefined herein appended to the parent molecular moiety through analkylene group of 1 to 4 carbons. Representative examples include, butare not limited to, trifluoromethoxymethyl, trifluoromethoxyethyl, etc.

The term “carbocyclic aryl,” as used herein, means phenyl or a bicyclicring system containing an aromatic ring wherein all of the ring membersof the bicyclic ring system are carbons. The bicyclic carbocyclic arylis naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, orindenyl. The phenyl and bicyclic carbocyclic aryls are attached to theparent molecular moiety through any carbon atom contained within thephenyl or bicyclic carbocyclic aryl.

The term “arene,” as used herein, means an optionally substitutedaromatic ring system. Representative examples include p-cymene, benzene,naphthalene, mesitylene, toluene, xylene, hexamethylbenzene, indane,biphenyl, etc.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora fused bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6membered ring containing at least one heteroatom independently selectedfrom the group consisting of O, N, and S. The 5-membered ring containstwo double bonds, and one, two, three, or four heteroatoms as ringatoms. The 6-membered ring contains three double bonds, and one, two,three or four heteroatoms as ring atoms. Representative examples ofmonocyclic heteroaryl include, but are not limited to, furanyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl is an 8- to 12-membered ring system having a monocyclicheteroaryl fused to an additional ring; wherein the additional ring maybe aromatic or partially saturated, and may contain additionalheteroatoms. Representative examples of bicyclic heteroaryl include, butare not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl,benzimidazolyl, benzodioxolyl, benzothienyl, chromenyl, furopyridinyl,indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine,quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, and2,3-dihydrofuro[3,2-b]pyridinyl. The monocyclic and the bicyclicheteroaryl groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the groups.

The term “cycloalkyl” as used herein, means a carbocyclic ring systemcontaining 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ringatoms, and zero double bonds. Examples of cycloalkyls include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The cycloalkyl groups of the presentinvention may contain an alkylene bridge of 1, 2, 3, or 4 carbon atoms,linking two non-adjacent carbon atoms of the group. Examples of suchbridged systems include, but are not limited to, bicyclo[2.2.1]heptanyland bicyclo[2.2.2]octanyl. The cycloalkyl groups described herein can beappended to the parent molecular moiety through any substitutable carbonatom.

The term “cycloalkenyl” as used herein, means a carbocyclic ring systemcontaining 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ringatoms, and one or two double bonds. Representative examples includecyclopentenyl, cyclohexenyl, etc.

The terms “arylalkyl,” “heteroarylalkyl,” “carbocyclic arylalkyl” andthe like refer to aryl, heteroaryl, or carbocyclic aryl groups, asdefined herein, appended to the parent molecular moiety through analkylene group of 1 to 4 carbons. Representative examples includebenzyl, phenethyl, imidazolylmethyl, indolylmethyl, pyridinylmethyl,etc.

The term “heterocycle,” “heterocyclic”, or “heterocyclyl” as usedherein, refers to a monocyclic heterocycle, a bicyclic heterocycle, or aspirocyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, 7,or 8-membered ring containing at least one heteroatom selected from O,N, or S. The 3 or 4 membered ring contains one heteroatom and optionallyone double bond. The 5-membered ring contains zero or one double bondand one, two or three heteroatoms. The 6, 7, or 8-membered ring containszero, one, or two double bonds, and one, two, or three heteroatoms.Representative examples of monocyclic heterocycle include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl,3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl,thiopyranyl, and trithianyl. The bicyclic heterocycle is a 5-12-memberedring system having a monocyclic heterocycle fused to a phenyl, asaturated or partially saturated carbocyclic ring, or another monocyclicheterocyclic ring. Representative examples of bicyclic heterocycleinclude, but are not limited to, 1,3-benzodioxol-4-yl,1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl,hexahydro-1H-furo[3,4-c]pyrrolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. Spirocyclicheterocycle or heterocyclyl means a 4, 5-, 6-, 7-, or 8-memberedmonocyclic heterocycle ring wherein two of the substituents on the samecarbon atom form a 3-, 4-, 5-, or 6-membered monocyclic ring selectedfrom the group consisting of cycloalkyl and heterocycle, each of whichis optionally substituted with 1, 2, 3, 4, or 5 alkyl groups. Examplesof a spiroheterocycle include, but are not limited to,1,3-diazaspiro[4.4]non-1-ene, 5-oxaspiro[3,4]octane and8-azaspiro[4.5]decane. The spirocyclic heterocycle may be substitutedsuch as, for example, with an oxo and/or C₁₋₆alkyl (e.g.,2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one). The monocyclic and bicyclicheterocycle groups of the present invention may contain an alkylenebridge of 1, 2, 3, or 4 carbon atoms, linking two non-adjacent atoms ofthe group. Examples of such a bridged heterocycle include, but are notlimited to, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl,1,2,3,4-tetrahydro-1,4-methanoisoquinolinyl, andoxabicyclo[2.2.1]heptanyl. The monocyclic, bicyclic, and spirocyclicheterocycle groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the group.

Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded bya designation indicating the number of atoms present in the group in aparticular instance (e.g., “C₁₋₆alkyl,” “C₃₋₆cycloalkyl,”“C₂₋₆alkynylene,” “C₂₋₆alkenylene”). These designations are used asgenerally understood by those skilled in the art. For example, therepresentation “C” followed by a subscripted number indicates the numberof carbon atoms present in the group that follows. Thus, “C₃alkyl” is analkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where arange is given, as in “C₁₋₆,” the members of the group that follows mayhave any number of carbon atoms falling within the recited range. A“C₁₋₆alkyl,” for example, is an alkyl group having from 1 to 6 carbonatoms, however arranged (i.e., straight chain or branched).

In some preferred embodiments of the invention, compounds contain one ormore protecting groups. A wide variety of protecting groups can beemployed in the methods of the invention. In general, protecting groupsrender chemical functionalities inert to specific reaction conditions,and can be appended to and removed from such functionalities in amolecule without substantially damaging the remainder of the molecule.Representative hydroxyl protecting groups, for example, are disclosed byBeaucage et al. (Tetrahedron 1992, 48, 2223-2311). Further hydroxylprotecting groups, as well as other representative protecting groups,are disclosed in Greene and Wuts, Protective Groups in OrganicSynthesis, Chapter 2, 2d ed., John Wiley & Sons, New York, 1991.Examples of hydroxyl protecting groups include, but are not limited to,t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,I-ethoxyethyl, 1-(2-chloroethoxy) ethyl, 2-trimethylsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenylmethyl, p,p′dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, acetate,chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.

2.0 Aryl-Aryl Coupling Processes

The present invention provides processes for forming a biaryl compoundin water by an ortho-directed ruthenium C—H insertion aryl-aryl couplingsequence. According to the first aspect of the invention, a first arylcompound is reacted with a second aryl compound in water in the presenceof a catalytically effective amount (e.g., about 0.01 to about 0.3equivalents) of a [RuCl₂(arene)]₂ complex and a source of formate. Thefirst aryl compound includes first and second ring atoms, the secondring atom being appended with a directing group and where the first ringatom is located in the ortho position with respect to the second ringatom and is the site of reaction with the second aryl compound. In turn,the second aryl compound includes a first ring atom that is substitutedwith a leaving group. The reaction between the first aryl compound andthe second aryl compound results in the formation of a carbon-carbonbond between the first ring atom of the first aryl compound and thefirst ring atom of the second aryl compound. The overall process may bedepicted as shown in equation (1), where Ar₁ is the first aryl compound,Ar₂ is the second aryl compound, DG is an ortho directing group, and Xis a suitable leaving group.

The DG may be appended to the second ring atom of the first aryl ring bydirect attachment, or may be appended to the second ring atom by anintervening linker, or may be attached in either of the precedingmanners and also have a second linker from the DG to a third ring atomof the first aryl ring so as to form an additional ring of 5- to7-members, such as the ring G:

In some embodiments according to the first aspect, the ortho directinggroup DG is —COR¹⁰, —COOR¹⁰—CONR⁷R⁸, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —OCONR⁷R⁸,—O-methoxymethyl (i.e., —OMOM), —SO₂R¹⁰, —SOR¹⁰, —SO₃H, —CH═NR¹¹,—SO₂NR⁷R⁸, —SONR⁷R⁸, —CN, —SO₂tBu, —CF₃, —NC, —OR¹⁰, —F, —Cl, Br, I,—S-Ph, —SR¹⁰, —NR⁷R⁸, —OP(O)OR¹⁰, —CH(OC₁₋₄alkyl)₂, —CH(OH)(NR⁷),

or a salt or protected derivative thereof, and R⁷, R⁸, R⁹, and R¹² areeach independently hydrogen, C₁₋₆alkyl, or C₁₋₆alkoxy, and R¹⁰ and R¹¹are each independently hydrogen or C₁₋₆alkyl; or R⁷, R⁸, R⁹, R¹⁰, R¹¹,and R¹² each, independently, form an alkylene or alkenylene linker to athird ring atom of the first aryl ring to form a 5- to 7-membered ringwherein one or more carbon atoms of the alkylene and alkenylene linkeris optionally replaced with an oxygen, sulfur, or nitrogen atom.

Representative examples of R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² forming analkylene/alkyenylene linker to a third ring atom of the first aryl ringinclude:

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted with one or more groups including, but not limitedto, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. In some embodiments,

is a partially unsaturated heterocycle substituted with C(O)R¹².Representative examples include

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted at a ring carbon and/or ring nitrogen with one ormore groups including, but not limited to, a protecting group,C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. Also as used herein,

is optionally substituted with an alkylene or alkenylene linker to athird ring atom of the first aryl ring to form a 5- to 7-membered ringwherein one or more carbon atoms of the alkylene and alkenylene isoptionally replaced with an oxygen, sulfur, or nitrogen atom. In someembodiments,

is a partially unsaturated heterocycle. In other embodiments,

is a 5-membered heteroaryl. Representative examples include

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted with one or more groups including, but not limitedto, a protecting group, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. Insome embodiments,

is a partially unsaturated heterocycle. Representative examples include

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted with one or more groups including, but not limitedto, a protecting group, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. Insome embodiments,

is a partially unsaturated heterocycle. Representative examples include

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted with one or more groups including, but not limitedto, a protecting group, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. Alsoas used herein,

is optionally substituted with an alkylene or alkenylene linker to athird ring atom of the first aryl ring to form a 5- to 7-membered ringwherein one or more carbon atoms of the alkylene and alkenylene isoptionally replaced with an oxygen, sulfur, or nitrogen atom. In someembodiments,

is a 5-membered heteroaryl. Representative examples include

The group

as used herein, includes 5- to 7-membered ring systems and may befurther substituted with one or more groups including, but not limitedto, a protecting group, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxy. Alsoas used herein,

is optionally substituted with an alkylene or alkenylene linker to athird ring atom of the first aryl ring to form a 5- to 7-membered ringwherein one or more carbon atoms of the alkylene and alkenylene isoptionally replaced with an oxygen, sulfur, or nitrogen atom. In someembodiments,

is a 6-membered heteroaryl. Representative examples include

In other embodiments

wherein R¹⁰⁰ is hydrogen or C₁₋₆alkyl. In other embodiments R¹⁰⁰together with a third atom of the first aryl compound forms a 5- to7-membered ring. In some embodiments, R¹⁰⁰ is an unsaturated bridge tothe third ring atom of the first aryl compound to form

where A² is the second ring atom of the first aryl compound, A³ is thethird ring atom of the first aryl compound, R¹⁴ is an optionalsubstituent and q is 0, 1, or 2.

In the foregoing embodiments, R¹³ and R¹⁴ are optional substituents thatinclude but are not limited to halogen, CN, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, C₁₋₄haloalkoxy, C₁₋₄ alkyl-S—, C₁₋₄alkylC(O)—,C₃₋₆cycloalkyl, C₁₋₄alkyl-O—C(O)—, C₁₋₄alkyl-NH—C(O)—, and(C₁₋₄alkyl)₂N—C(O)—.

In the foregoing embodiments, p may be any integer or range of integerswithin the range from 0 to 5.

In some embodiments the directing group is selected from the groupconsisting of:

or a salt or protected derivative thereof.

In other embodiments, the directing group is selected from

wherein R¹⁰⁰ together with the second ring atom and third ring atom ofthe first aryl compound forms

In some embodiments, the directing group DG is directly substituted onthe second ring atom of the first aryl compound without an interveninglinker. For example, as shown below, an oxazoline DG is directlysubstituted on the second ring atom of Ar₁.

In other embodiments, as shown below, DG is directly substituted on thesecond ring atom of the first aryl compound with additional ring fusionto the third ring atom, where G represents the additional fused ring andthe DG is the embedded pyridine ring:

In other embodiments, the directing group is appended to the second ringatom of the first aryl compound by an intervening linker L¹, wherein L¹is a chain comprising 1-5 atoms selected from carbon, nitrogen, oxygen,or sulfur or L¹ is a ring selected from C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl, orheteroaryl, the C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, and cyano.

For example, the directing group —NR⁷R⁸ may be appended to the secondring atom by a chain that includes oxygen and carbon atoms such as whereL¹ is —OCH₂CH₂— and L¹-DG is —OCH₂CH₂—NR⁷R⁸.

In another example, the oxy anion directing group —O⁻ may be appended tothe second ring atom by an alkylene chain, such as where L¹ is CH₂ andL¹-DG is —CH₂—O⁻.

In some embodiments together with the foregoing, the leaving group onthe second aryl compound is bromo, chloro, iodo, or other suitablederivative. Preferably, the leaving group is bromo.

In still other embodiments in combination with the foregoing, theformate source is an alkali metal formate (e.g., sodium formate),alkaline earth metal formate (e.g., magnesium formate), N(R²⁰)₄HC(O)O,HC(O)—OC₁₋₆ alkyl, NaCHSO (sodium thioformate), sodium formamide,CHO—COOH (glyoxal), sodium glyoxalate or potassium glyoxalates, or acombination thereof; and R²⁰ is hydrogen or C₁₋₆alkyl. For example, insome embodiments, the formate source is lithium formate, sodium formate,potassium formate, or cesium formate. In some embodiments, the formatesource is magnesium formate or calcium formate. In certain preferredembodiments, the formate source is sodium formate. In still otherembodiments, the formate source is preferably ammonium formate.

In yet other embodiments in combination with the foregoing, the firstaryl compound comprises a first 6-membered carbocyclic ring, the first6-membered carbocyclic ring having the first and second ring atoms ofthe first aryl compound. For example, the first aryl compound maycomprise a phenyl ring or substituted phenyl ring.

In yet other embodiments in combination with the foregoing, the secondaryl compound comprises a second 6-membered carbocyclic ring, the second6-membered carbocyclic ring comprising the first ring atom of the secondaryl compound. For example, the second aryl compound may comprise aphenyl ring or substituted phenyl ring.

In yet other embodiments in combination with the foregoing, the firstaryl compound comprises a 5-6-membered heteroaryl ring, the 5-6-memberedheteroaryl ring comprising the first and second ring atoms of the firstaryl compound and the first ring atom of the first aryl compound is acarbon atom. For example, the first aryl compound may comprise apyridine, thiophene, or furan ring.

In yet other embodiments in combination with the foregoing, the secondaryl compound comprises a 5-6-membered heteroaryl ring, the 5-6-memberedheteroaryl ring comprising the first ring atom of the second arylcompound and the first ring atom of the second aryl compound is a carbonatom. For example, the second aryl compound may comprise a pyridine,thiophene, or furan ring.

In certain embodiments, the first aryl compound is

wherein DG is the directing group; L² is a bond or L¹; L¹ is a chaincomprising 1-5 atoms selected from carbon, nitrogen, oxygen, or sulfur;or L¹ is a ring selected from C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R³ and R⁵ at each occurrence, are independently hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl (e.g. CFH₂, CF₃ orCClF₂), C₁₋₆alkoxyalkyl, C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro,OR⁴⁰, COOR⁴⁰, CONR⁴¹R⁴², SO₂NR⁴¹R⁴², C(O)R⁴⁰, SO₂R⁴⁰, SR⁴⁰,C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl, the C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, and cyano; R⁴⁰, R⁴¹, and R⁴² are each independentlyhydrogen or C₁₋₆alkyl; and c is 0 to 3. In a group of compoundsaccording to this embodiment, L² is a bond and DG is

or a salt or protected derivative thereof. In a subgroup of compounds,DG is

or a salt or protected derivative thereof.

In particular embodiments, the first aryl compound is

or a salt or protected derivative thereof.

In some embodiments, the second aryl compound is

wherein R⁴, at each occurrence, is independently hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰, CH₂OPG, COOR⁵⁰,CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰, C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl,heteroaryl, spirocyclic heterocyclylC₁₋₄alkyl, carbocyclicarylC₁₋₄alkyl, or heteroarylC₁₋₄alkyl, the C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, spirocyclic heterocyclyl,carbocyclic aryl, or heteroaryl being optionally substituted with one ormore substituents independently selected from the group consisting ofoxo, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,OR⁶⁰, CH₂OPG, CHO, COOR⁶⁰, and cyano; PG, at each occurrence, isindependently a protecting group; X is chloro, bromo, or iodo; R⁵⁰, R⁵¹,and R⁵² are each independently, hydrogen or C₁₋₆alkyl; each R⁶⁰ isindependently H, C₁₋₆alkyl, or 3-8-membered heterocyclylC₁₋₄alkyl, the3-8-membered heterocyclyl moiety being optionally substituted withC₁₋₆alkyl; and b is 0 to 5.

In one group of compounds, the second aryl compound is

wherein X is chloro, bromo, or iodo; R^(4a) is C₁₋₆alkoxy; R^(4b) isC₁₋₆alkyl; and R^(4c) is fluoro. In a subgroup of compounds, R^(4a) ismethoxy; and R^(4b) is isopropyl.

In another group of compounds, the second aryl compound is

wherein: X is chloro, bromo, or iodo; and R⁴ is hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl, CH₂OPG, COOR⁵⁰,1,3-diazaspiro[4.4]non-1-en-4-one-3-yl-CH₂—, imidazolylCH₂—, orbenzimidazolylCH₂—, the 1,3-diazaspiro[4.4]non-1-en-4-one-3-yl beingoptionally substituted with C₁₋₆alkyl, the imidazolyl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, halogen, CH₂OPG, and CHO, and thebenzimidazolyl being optionally substituted with one or moresubstituents independently selected from the group consisting of OR⁶⁰and COOR⁶⁰; PG, at each occurrence, is independently a protecting group;R⁵⁰ is independently hydrogen or C₁₋₆alkyl; and each R⁶⁰ isindependently hydrogen, C₁₋₆alkyl, or 5-membered heterocyclylCH₂—, the5-membered heterocyclyl moiety being a 1,3-dioxol-2-one and optionallysubstituted with C₁₋₆alkyl. In a subgroup of compounds, R⁴ is methyl,CH₂OPG, CH₂halogen, COOR⁵⁰,

In a further subgroup, each R⁶⁰ is independently C₁₋₆alkyl or

In still other embodiments, the second aryl compound is

wherein X¹ is O or S; R⁴, at each occurrence, is independently hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰, CH₂OPG, COOR⁵⁰,CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰, C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl,heteroaryl, carbocyclic arylC₁₋₄alkyl, or heteroarylC₁₋₄alkyl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, OR⁶⁰,COOR⁶⁰, and cyano; PG is a protecting group; X is chloro, bromo, oriodo; R⁵⁰, R⁵¹, R⁵², and R⁶⁰ are each independently hydrogen orC₁₋₆alkyl; and b is 0 to 2.

In some embodiments, the biaryl compound produced by the method of theinvention is

wherein DG is the directing group; L² is a bond or L¹; L¹ is a chaincomprising 1-5 atoms selected from carbon, nitrogen, oxygen, or sulfur;or L¹ is a ring selected from C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R³ and R⁵ at each occurrence, are independently, hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl (e.g. CFH₂, CF₃ orCClF₂), C₁₋₆alkoxyalkyl, C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro,OR⁴⁰, COOR⁴⁰, CONR⁴¹R⁴², SO₂NR⁴¹R⁴², C(O)R⁴⁰, SO₂R⁴⁰, SR⁴⁰,C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl, the C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, and cyano; R⁴, at each occurrence, is independentlyhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl,C₁₋₆alkoxyalkyl, C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰,CH₂OPG, COOR⁵⁰, CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰,C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, heteroaryl, spirocyclic heterocyclylC₁₋₄alkyl, carbocyclicarylC₁₋₄alkyl, or heteroarylC₁₋₄alkyl, the C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, spirocyclic heterocyclyl,carbocyclic aryl, or heteroaryl being optionally substituted with one ormore substituents independently selected from the group consisting ofoxo, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,OR⁶⁰, COOR⁶⁰, CH₂OPG, CHO, and cyano; PG, at each occurrence isindependently a protecting group; R⁴⁰, R⁴¹, R⁴², R⁵⁰, R⁵¹, and R⁵² areeach independently hydrogen or C₁₋₆alkyl; each R⁶⁰ is independently H,C₁₋₆alkyl, or 3-8-membered heterocyclylC₁₋₄alkyl, the 3-8-memberedheterocyclyl moiety being optionally substituted with C₁₋₆alkyl; b is 0to 5; and c is 0 to 3.

In certain embodiments, the biaryl compound produced by the method ofthe invention is

wherein DG, L², R³, R⁵, and c are as defined elsewhere herein and R⁴ ishydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl, CH₂OPG, COOR⁵⁰,1,3-diazaspiro[4.4]non-1-en-4-one-3-yl-CH₂—, imidazolylCH₂—, orbenzimidazolylCH₂—, the 1,3-diazaspiro[4.4]non-1-en-4-one-3-yl beingoptionally substituted with C₁₋₆alkyl, the imidazolyl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, halogen, CH₂OPG, and CHO, and thebenzimidazolyl being optionally substituted with one or moresubstituents independently selected from the group consisting of OR⁶⁰and COOR⁶⁰; PG, at each occurrence, is independently a protecting group;R⁵⁰ is independently hydrogen or C₁₋₆alkyl; and each R⁶⁰ isindependently hydrogen, C₁₋₆alkyl, or 5-membered heterocyclylCH₂—, the5-membered heterocyclyl moiety being a 1,3-dioxol-2-one and optionallysubstituted with C₁₋₆alkyl. In a subgroup of compounds, R⁴ is methyl,CH₂OPG, CH₂halogen, COOR⁵⁰,

In a further subgroup, each R⁶⁰ is independently C₁₋₆alkyl or

In one group of compounds, the biaryl compound is

DG is

and R¹³ and p are as defined elsewhere herein. In a subgroup, DG is

In another group of compounds, the biaryl compound is

or a salt or protected derivative thereof, and R⁴ is methyl, CH₂OPG,CH₂halogen, COOR⁵⁰, or

In certain embodiments according to this aspect of the invention, thereaction of the first aryl compound with the second aryl compound may beconducted at a temperature above ambient temperature. For example, thereaction may be conducted at temperatures from about 50 to about 100° C.or at reflux.

In certain embodiments according to this aspect of the invention, thereaction of the first aryl compound with the second aryl compound may beconducted in the presence of a base such as, for example, tertiaryamines, pyridines and alkali metal acetates, alkali metal hydroxides,alkali metal alkoxides, alkali metal phosphates, alkali metalcarbonates, and alkali metal hydrogen carbonates. More preferably, thebase is chosen from NaOAc, KOAc, K₂CO₃, Na₂CO₃, CaCO₃, K₃PO₄, NaHCO₃,CsOAc, MesCOOK, C₅H₉KO₂ (potassium pivalate), C₅H₉NaO (sodium pivalate),or trialkylamines, or mixtures thereof, in which the alkyl groups eachpreferably contain, independently of each other, 1 to 20, in particular1 to 10 carbon atoms, for example triethylamine, tri(n-butyl)amine,methyldiisopropylamine or methyldicyclohexylamine. In certainembodiments, the base is potassium carbonate.

In certain embodiments, the reaction may be conducted exposed to theambient atmosphere (i.e., not under an inert atmosphere).

In certain embodiments, the [RuCl₂(arene)]₂ complex is[RuCl₂(benzene)]₂, [RuCl₂(p-cymene)]₂, [RuCl₂(hexamethylbenzene)]₂,[RuCl₂(biphenyl)]₂, [RuCl₂(mesitylene)]₂, or [RuCl₂(indane)]₂. Incertain preferred embodiments, the [RuCl₂(arene)]₂ complex is[RuCl₂(p-cymene)]₂.

In still other embodiments, the reaction of the first aryl compound withthe second aryl compound may be conducted in the presence of aco-solvent. For example, the co-solvent includes, but is not limited to,ethanol, methanol, isopropanol, acetone, butanol, methylethylketone,acetonitrile, N-methylpyrrolidinone, or N,N-dimethylformamide, ormixtures thereof.

3.0 Ruthenium Catalysts

In a second aspect of the invention are provided ruthenium catalystsprepared by the reaction of a [RuCl₂(arene)]₂ complex with a source offormate. For example, catalysts prepared from [RuCl₂(arene)]₂ and aformate source may be prepared by reacting a [RuCl₂(arene)]₂ complexwith ammonium formate. Alternatively, a [RuCl₂(arene)]₂ complex may bereacted with sodium formate to form the ruthenium catalysts of theinvention. Other sources of formate include those described elsewhereherein. Likewise, suitable arenes include those described elsewhereherein (e.g., [RuCl₂(p-cymene)]₂).

In certain embodiments, the ruthenium catalyst of the invention isprepared from [RuCl₂(arene)]₂ and a formate source and used in situ. Inother embodiments, the ruthenium catalyst prepared from [RuCl₂(arene)]₂and a formate source may be isolated and optionally purified prior touse.

In certain embodiments, the ruthenium catalyst prepared from[RuCl₂(arene)]₂ and a formate source is formed in situ by reacting 1part of a [RuCl₂(arene)]₂ complex with about 5 to about 15 parts of asource of formate. The in situ formation of the ruthenium catalyst maybe carried out in aqueous media in the presence of an optional base(e.g., potassium carbonate) and the first and second aryl compounds, andmay optionally include the application of heat. Optionally the base(e.g., potassium carbonate) may be added (about 1 to about 3equivalents). The optional bases include those described elsewhereherein.

In certain embodiments, the ruthenium catalyst prepared from[RuCl₂(arene)]₂ and a formate source may be prepared and isolated andoptionally purified. When separately preparing and isolating theruthenium catalyst, 1 part of a [RuCl₂(arene)]₂ may be reacted withabout 1 to about 15 parts of a source of formate. In certainembodiments, about 1 part to about 5 parts of the source of formate maybe used. In a preferred embodiment, about 4 parts of the source offormate may be used.

When preparing the ruthenium catalyst prepared from [RuCl₂(arene)]₂ anda formate source for isolation, organic solvents (e.g., dichloromethane)may be used when mixing the reactants and the reaction may be conductedat room temperature. The ruthenium catalyst may be isolated byconcentrating the reaction mixture and precipitating/crystallizing theproduct by the addition of a non-polar solvent (e.g., hexane). Theproduct may be collected, washed with a suitable organic solvent (e.g.,diethyl ether) and dried. In certain embodiments, the reaction may beconducted under an ambient atmosphere and/or with the exclusion ofmoisture. This catalyst may be used to prepare useful aryl-arylcompounds. The isolated catalyst may alleviate the need to useadditional amounts of [RuCl₂(arene)]₂ or formate.

4.0 Compounds Comprising a 1,2,4-oxadiazol-5(4H)-one and Processes forPreparing Biaryls Therefrom

In a third aspect of the invention are provided methods of preparing abiaryl compound comprising reacting a first aryl compound with a secondaryl compound in the presence of a catalytically effective amount of a[RuCl₂(arene)]₂ complex; the first aryl compound comprising first andsecond ring atoms, the second ring atom being appended with a directinggroup

or a salt or protected derivative thereof, and the second ring atombeing located ortho to the first ring atom; the second aryl compoundcomprising a first ring atom, the first ring atom being substituted witha leaving group; wherein the reacting of the first aryl compound withthe second aryl compound forms a bond between the first ring atom of thefirst aryl compound and the first ring atom of the second aryl compound.

It will be understood by one skilled in the art that the DG

according to each of the aspects of the present invention, may exist indifferent tautomeric forms:

In some embodiments, the first aryl compound is

wherein DG is

or a salt or protected derivative thereof; L² is a bond or L¹; L¹ is achain comprising 1-5 atoms selected from carbon, nitrogen, oxygen, orsulfur; or L¹ is a ring selected from C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R³ and R⁵ at each occurrence, are independently, hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁴⁰, COOR⁴⁰, CONR⁴¹R⁴²,SO₂NR⁴¹R⁴², C(O)R⁴⁰, SO₂R⁴⁰, SR⁴⁰, C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R⁴⁰, R⁴¹, and R⁴² are each independently, hydrogen or C₁₋₆alkyl;and c is 0 to 3.

In other embodiments, the first aryl compound is

or a salt or protected derivative thereof.

In still other embodiments, the second aryl compound is

wherein R⁴, at each occurrence, is independently hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰, CH₂OPG, COOR⁵⁰,CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰, C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl,heteroaryl, carbocyclic arylC₁₋₄alkyl, or heteroarylC₁₋₄alkyl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, OR⁶⁰,CH₂OPG, CHO, COOR⁶⁰, and cyano; PG, at each occurrence, is independentlya protecting group; X is chloro, bromo, or iodo; R⁵⁰, R⁵¹, and R⁵² areeach independently, hydrogen or C₁₋₆alkyl; each R⁶⁰ is independently H,C₁₋₆alkyl, or 3-8-membered heterocyclylC₁₋₄alkyl, the 3-8-memberedheterocyclyl moiety being optionally substituted with C₁₋₆alkyl; and bis 0 to 5.

In yet other embodiments, the second aryl compound is

wherein: X is chloro, bromo, or iodo; and R⁴ is C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl, CH₂OPG, COOR⁵⁰, imidazolylCH₂—, orbenzimidazolylCH₂—, the imidazolyl being optionally substituted with oneor more substituents independently selected from the group consisting ofC₁₋₆alkyl, halogen, CH₂OPG, and CHO, and the benzimidazolyl beingoptionally substituted with one or more substituents independentlyselected from the group consisting of OR⁶⁰ and COOR⁶⁰; R⁵⁰ isindependently hydrogen or C₁₋₆alkyl; and each R⁶⁰ is independentlyhydrogen, C₁₋₆alkyl, or 5-membered heterocyclylCH₂—, the 5-memberedheterocyclyl moiety being a 1,3-dioxol-2-one and optionally substitutedwith C₁₋₆alkyl. In one group of compounds, R⁴ is methyl, CH₂OPG,CH₂halogen, COOR⁵⁰, or

In a further subgroup, each R⁶⁰ is independently C₁₋₆alkyl or

In some embodiments, the biaryl compound is

wherein DG is

or a salt or protected derivative thereof; L² is a bond or L¹; L¹ is achain comprising 1-5 atoms selected from carbon, nitrogen, oxygen, orsulfur; or L¹ is a ring selected from C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R³ and R⁵ at each occurrence, are each independently, hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁴⁰, COOR⁴⁰, CONR⁴¹R⁴²,SO₂NR⁴¹R⁴², C(O)R⁴⁰, SO₂R⁴⁰, SR⁴⁰, C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R⁴, at each occurrence, is independently hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰, CH₂OPG, COOR⁵⁰,CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰, C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl,heteroaryl, or heteroarylCH₂—, the C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl beingoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, OR⁶⁰, COOR⁶⁰, CH₂OPG, CHO,′ and cyano; PG,at each occurrence, is independently a protecting group; R⁴⁰, R⁴¹, R⁴²,R⁵⁰, R⁵¹, and R⁵² are each independently hydrogen or C₁₋₆alkyl; each R⁶⁰is independently H, C₁₋₆alkyl, or 3-8-membered heterocyclylC₁₋₄alkyl,the 3-8-membered heterocyclyl moiety being optionally substituted withC₁₋₆alkyl; b is 0 to 5; and c is 0 to 3.

In certain embodiments, the biaryl compound produced by the method ofthe invention is

wherein L², R³, R⁵, and c are as defined elsewhere herein; DG is

or a salt or protected derivative thereof; and R⁴ is hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl, CH₂OPG, COOR⁵⁰,imidazolylCH₂—, or benzimidazolylCH₂—, the imidazolyl being optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, halogen, CH₂OPG, and CHO, and thebenzimidazolyl being optionally substituted with one or moresubstituents independently selected from the group consisting of OR⁶⁰and COOR⁶⁰; PG, at each occurrence, is independently a protecting group;R⁵⁰ is independently hydrogen or C₁₋₆alkyl; and each R⁶⁰ isindependently hydrogen, C₁₋₆alkyl, or 5-membered heterocyclylCH₂—, the5-membered heterocyclyl moiety being a 1,3-dioxol-2-one and optionallysubstituted with C₁₋₆alkyl. In a subgroup of compounds, R⁴ is methyl,CH₂OPG, CH₂halogen, COOR⁵⁰, or

In a further subgroup, each R⁶⁰ is independently C₁₋₆alkyl or

In certain embodiments, the biaryl compound is

or a salt or protected derivative thereof; and R⁴ is methyl, CH₂OPG,CH₂halogen, COOR⁵⁰, or

In a subgroup, each R⁶⁰ is independently C₁₋₆alkyl or

In other embodiments according to the third aspect are biaryl compoundsof the invention of formula

or salt thereof, wherein; DG is

or a salt or protected derivative thereof; L² is a bond or L¹; L¹ is achain comprising 1-5 atoms selected from carbon, nitrogen, oxygen, orsulfur; or L¹ is a ring selected from C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R³ and R⁵ at each occurrence, are each independently, hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁴⁰, COOR⁴⁰, CONR⁴¹R⁴²,SO₂NR⁴¹R⁴², C(O)R⁴⁰, SO₂R⁴⁰, SR⁴⁰, C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl, theC₃₋₈cycloalkyl, C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclicaryl, or heteroaryl being optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, andcyano; R⁴, at each occurrence, is independently hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alknynyl, C₁₋₆haloalkyl, C₁₋₆alkoxyalkyl,C₁₋₆haloalkoxyalkyl, halogen, cyano, nitro, OR⁵⁰, CH₂OPG, COOR⁵⁰,CONR⁵¹R⁵², SO₂NR⁵¹R⁵², C(O)R⁵⁰, SO₂R⁵⁰, SR⁵⁰, C₃₋₈cycloalkyl,C₅₋₈cycloalkenyl, 3-8-membered heterocyclyl, carbocyclic aryl,heteroaryl, or heteroarylCH₂—, the C₃₋₈cycloalkyl, C₅₋₈cycloalkenyl,3-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl beingoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, OR⁶⁰, CH₂OPG, CHO,′ and cyano; PG, at eachoccurrence, is independently a protecting group; R⁴⁰, R⁴¹, R⁴², R⁵⁰,R⁵¹, R⁵², and R⁶⁰ are each independently hydrogen or C₁₋₆alkyl; b is 0to 5; and c is 0 to 3. In one group of compounds a biaryl compound ofthe invention is

or a salt or optionally protected derivative thereof; and R⁴ is methyl,CH₂OPG, CH₂halogen, or COOR⁵⁰.

The group

may be substituted with a suitable protecting group such as, forexample, a benzyl protecting group. Suitable benzyl protecting groupsmay include without limitation benzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, etc.

In certain embodiments, the methods according to this aspect of theinvention may be conducted in an organic solvent. In certain embodiment,the organic solvent is N-methylpyrrolidinone, N,N-dimethylformamide, orN,N-dimethylacetamide, or mixtures thereof.

In other embodiments, the methods according to this aspect of theinvention may be conducted in the presence of a source of formate,including those described hereinabove.

In other embodiment, the methods according to this aspect of theinvention may be conducted in the presence of a base, such as thosedescribed hereinabove.

5.0 Preparation and Use of Biaryl Compounds

Biaryl compounds III may be prepared according to the process depictedin Scheme 1, wherein R³, R⁴, R⁵, L², DG, X, b, and c are as definedherein.

The process of Scheme 1 may be carried out by reacting formula I (1equivalent) with formula II (about 1 to about 4 equivalents), in thepresence of a catalytically effective amount (e.g., about 0.01 to about0.3 equivalents) of [RuCl₂(arene)]₂ complex (e.g., [RuCl₂(p-cymene)]₂)and a source of formate (about 1 to about 2 equivalents) in water.Optionally a base (e.g., potassium carbonate) may be added (about 1 toabout 3 equivalents). The reaction may be heated up to about reflux andmay be conducted under an insert atmosphere or exposed to the ambientatmosphere. The concentration of formula I may be about 0.1 M to about 1M, although other concentrations may also be used, depending on theparticular reaction.

Examples of suitable bases are mentioned in for example “Metal-catalyzedCross-coupling reactions”, F. Diederich and P. J. Stang Eds., Wiley-VCH,Weinheim, 1998, Chapters 2 and 3. The base is preferably chosen from thegroup of tertiary amines, pyridines and alkali metal acetates, alkalimetal hydroxides, alkali metal alkoxides, alkali metal phosphates,alkali metal carbonates, and alkali metal hydrogen carbonates. Morepreferably, the base is chosen from NaOAc, KOAc, K₂CO₃, Na₂CO₃, CaCO₃,K₃PO₄, NaHCO₃, CsOAc, MesCOOK, C₅H₉KO₂ (potassium pivalate), C₅H₉NaO(sodium pivalate), or trialkylamines, in which the alkyl groups eachpreferably contain, independently of each other, 1 to 20, in particular1 to 10 carbon atoms, for example triethylamine, tri(n-butyl)amine,methyldiisopropylamine or methyldicyclohexylamine.

The reaction depicted in Scheme 1 may also be conducted by preparing aruthenium catalyst formed from [RuCl₂(arene)]₂ complex and a source offormate separately and adding a catalytically effective amount of theisolated ruthenium catalyst product to the reaction mixture rather thanforming the ruthenium catalyst product in situ.

The process depicted in Scheme 1 is merely exemplary. Biaryl compoundswhere either the first aryl compound and/or the second aryl compound isa heteroaryl may be prepared using the illustrated process.

Biaryl compounds produced using the processes of the invention may beuseful as intermediates in the synthesis of biologically activebiaryl-containing molecules.

Depicted in Scheme 2 is a synthetic sequence through which the biarylcompound 1, produced using the processes of the invention, may beconverted to compound 5, anacetripib. Anacetripib is an inhibitor ofcholesterol ester transfer protein (CETP), which is a plasmaglycoprotein that transfers cholesterol ester (CE) from HDL to LDL andVLDL, thereby lowering antiatherogenic HDL and increasingpro-atherogenic LDL and VLDL.

Depicted in Scheme 3 is a synthetic sequence through which the biarylcompound 6, which may be produced from 4-bromotoluene and compound 11using the processes of the invention, may be converted to compound 9,azilsartan medoxomil. Edarbi (azilsartan medoxomil), a prodrug, ishydrolyzed to azilsartan in the gastrointestinal tract duringabsorption. Azilsartan is a selective AT1 subtype angiotensin IIreceptor antagonist. In Scheme 3, the methyl group in 6 may befunctionalized such as by benzylic bromination or oxidation to acorresponding benzyl bromide or alcohol. Alternatively, the methyl maybe oxidized to the acid and then reduced to the alcohol using knowntechniques. As a further alternative, a compound 10 may be coupled with11 using the methods of the invention to produce 7. In compound 10, Y¹may be a protected oxygen (e.g., O-benzyl, O-TBDMS, OMOM, etc.). Incompound 7, when Y² is a protected oxygen, the protecting group may beremoved using standard conditions in order to form the correspondingalcohol. And when Y² is an alcohol, the alcohol may be converted to asuitable leaving group (e.g., OTs) for further reaction to 8.

Depicted in Scheme 4 is a further alternative process where 11 may bereacted with 12 to directly produce 8.

It will be understood by one skilled in the art that additionalprotecting groups may be required to efficiently carry out certaintransformations in Schemes 3 and 4. It is within the level of ordinaryskill to be able to select such protecting groups. For example, themoiety

may be substituted with a protecting group as described elsewhereherein.

Similar processes and techniques may be employed to convert 13 to abiaryl intermediate 14 and ultimately to 15, losartan. Related usefulcompounds such as marketed drugs irbesartan, olmesartan and valsartanmay be prepared using the similar process and techniques.

Alternatively the following intermediates may be used for thecondensation and later the cyano group may be converted to a tetrazolemoiety for preparation of these drugs:

Alternatively, simple aryl tetrazole (appropriately protected withgroups such a trityl) and cyano compounds, as illustrated below, mayalso be condensed with bromo intermediates such as3-(4-bromobenzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (below), inthe synthesis of one such drug example—irbesartan(2-butyl-3-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1,3-diazaspiro[4.4]non-1-en-4-one)(see below):

The above two intermediates may be condensed with the followingintermediate3-(4-bromobenzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one:

to prepare a biaryl compound, which may subsequently be converted toirbesartan.

6.0 Examples 6.1 C—H Insertion and Coupling with In-Situ GeneratedRuthenium Catalyst from [RuCl₂(p-cymene)]₂ and a Source of FormateExample 1

A mixture of 2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (88 mg,0.41 mmol), bromobenzene (242 mg, 1.54 mmol), sodium formate (50 mg,0.73 mmol), K₂CO₃ (205 mg, 1.48 mmol), and [RuCl₂(p-cymene)]₂ (44 mg,0.072 mmol) was vacuumed and purged with argon three times. A sample offreshly distilled H₂O (2 mL) that was vacuumed and purged with argon wasadded to the reaction mixture. After final vacuum and argon purge, theheterogeneous mixture was allowed to heat at reflux (oil bathtemperature: 110° C.). After 18 h, TLC showed quantitative conversion.The dark black reaction mixture was cooled down to room temperature andpassed through a small Celite column (50 g). The celite was washed withadditional EtOAc (10 mL). The Filtrate was concentrated under reducedpressure to a crude mixture which was purified by gradient SiO₂ columnchromatography (5-20% EtOAc/hex) to give isolated yield of 60 mg product2-(4-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-4,5-dihydrooxazole. ¹H NMR(500 MHz, CDCl3) δ 3.9 (m, 2H), 4.2 (m, 2H), 7.3-7.7 (m, 5H), 7.51 (d,1H), 7.77 (m, 1H), 8.1 (m, 1H); LRMS (EI) m/z 292.

Example 2

A mixture of 2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (41 mg,0.19 mmol), 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (47 mg, 0.19mmol), sodium formate (20 mg, 0.29 mmol), K₂CO₃ (90 mg, 0.65 mmol), and[RuCl₂(p-cymene)]₂ (28 mg, 0.045 mmol) was vacuumed and purged withargon three times. A sample of freshly distilled H₂O (2 mL) that wasvacuumed and purged with argon was added to the reaction mixture. Afterfinal vacuum and argon purge, the heterogeneous mixture was allowed toheat at reflux (oil bath temperature: 110° C.). After 16 h, TLCmonitoring showed quantitative conversion. The dark black reactionmixture was cooled down to room temperature and passed through a smallCelite column (50 g). The celite was washed with additional EtOAc (75mL). The Filtrate was concentrated under reduced pressure to a crudemixture which was purified by gradient SiO₂ column chromatography (5-20%EtOAc/hex) to afford isolated yield of 32 mg of the product2-(4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-4,5-dihydrooxazole.¹H NMR (500 MHz, CDCl3) δ 1.24 (d, 6H), 3.2 (m, 1H), 3.7 (s, 3H), 3.9(dd, 2H), 4.15 (dd, 2H), 6.6 (d, 1H), 7.15 (d, 1H), 7.49 (d, 1H), 7.73(d, 1H), 8.13 (s, 1H); HRMS (EI) calc 382.14188, obtained 382.14301.

Example 3

A mixture of 2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (41 mg,0.19 mmol), 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (47 mg, 0.19mmol), NH₄HCO₂ (20 mg, 0.32 mmol), K₂CO₃ (90 mg, 0.65 mmol), and[RuCl₂(p-cymene)]₂ (30 mg, 0.049 mmol) was vacuumed and purged withargon three times. A sample f freshly distilled H₂O (2 mL) that wasvacuumed and purged with argon was added to the reaction mixture. Afterfinal vacuum and argon purge, the heterogeneous mixture was allowed toheat at reflux (oil bath temperature: 110° C.). After 16 h, TLC showedquantitative conversion. The dark black reaction mixture was cooled downto room temperature and passed through a small Celite column (50 g). Thecelite was washed with additional EtOAc (75 mL). The Filtrate wasconcentrated under reduced pressure to a crude mixture which waspurified by gradient SiO₂ column chromatography (5-20% EtOAc/hex) toafford isolated yield of 43 mg of the product2-(4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-4,5-dihydrooxazole.¹H NMR (500 MHz, CDCl3) δ 1.24 (d, 6H), 3.2 (m, 1H), 3.7 (s, 3H), 3.9(dd, 2H), 4.15 (dd, 2H), 6.6 (d, 1H), 7.15 (d, 1H), 7.49 (d, 1H), 7.73(d, 1H), 8.13 (s, 1H).

Example 4

A mixture of benzo[h]quinoline (115 mg, 0.64 mmol), bromobenzene (241mg, 1.53 mmol), NH₄HCO₂ (35 mg, 0.55 mmol), K₂CO₃ (202 mg, 1.46 mmol),and [RuCl₂(p-cymene)]₂ (40 mg, 0.065 mmol) was vacuumed and purged withargon three times. A sample of freshly distilled H₂O (2 mL) that wasvacuumed and purged with argon was added to the reaction mixture. Afterfinal vacuum and argon purge, the heterogeneous mixture was allowed toheat at reflux (oil bath temperature: ˜110° C. for 18 hours). The darkblack reaction mixture was cooled down to room temperature and passedthrough a small Celite column (50 g). The celite was washed withadditional EtOAc (40 mL). The Filtrate was concentrated under reducedpressure to a crude mixture which was purified by gradient SiO₂ columnchromatography (5-15% EtOAc/hex) to afford 87 mg of the product10-phenylbenzo[h]quinolone. ¹H NMR (500 MHz, CDCl3) δ 7.38 (dd, 1H),7.40 (m, 5H), 7.55 (dd, 1H), 7.68 (d, 1H), 7.70-7.82 (dd, 2H), 7.93 (dd,1H), 8.10 (dd, 1H), 8.42 (dd, 1H); HRMS (EI) calc 254.09697, obtained254.09666.

Example 5

2-Phenylpyridine (178 mg, 1.14 mmol), 4-bromotoluene (412 mg, 2.408mmol), HCOONH₄ (75 mg, 1.20 mmol), K₂CO₃ (160 mg, 1.2 mmol), and[RuCl₂(p-cymene)]₂ (55 mg, 0.089 mmol) in a 25 mL RBF were mixed withdeionized H₂O (2 mL). After mixing the heterogeneous mixture was allowedto heat at reflux (oil bath temperature: 110° C.) for 13 hours. The TLCanalysis indicated ˜90% conversion as a mixture of mono and diarylatedphenyl pyridine. No inert atmosphere was necessary—all manipulationswere done without seal tubes or pressure reactors.

6.2 C—H Insertion and Coupling without Base Example 6

A mixture of 2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (100 mg,0.46 mmol), bromobenzene (250 mg, 1.59 mmol), NaHCO₂ (52 mg, 0.76 mmol)and [RuCl₂(p-cymene)]₂ (50 mg, 0.081 mmol) was vacuumed and purged withargon for 10 minutes. A sample of freshly distilled H₂O (2 mL) that wasvacuumed and purged with argon was added to the reaction mixture. Afterfinal vacuum and argon purge, the heterogeneous mixture was allowed toheat at reflux (oil bath temperature: 100° C.-105° C.). After 18 h, thedark black reaction mixture showed ˜90% conversion.

Example 7

A 25 mL round bottom flask was degassed by removing air and purging withargon for 5 minutes. A mixture of benzo[h]quinoline (130 mg, 0.72 mmol),bromobenzene (241 mg, 1.53 mmol), HCOONH₄ (50 mg, 0.79 mmol), and[RuCl₂(p-cymene)]₂ (45 mg, 0.07 mmol) were added. A sample of freshlydistilled H₂O (2 mL) that was vacuumed and purged with argon was addedto the reaction mixture. After final vacuum and argon purge, theheterogeneous mixture was allowed to heat at reflux (oil bathtemperature: 100° C.) for 22 hours. TLC revealed that a spotcorresponding to desired product previously established was formed about50% based on analysis.

6.3 Isolated Ruthenium Catalyst from [RuCl₂(p-cymene)]₂ and FormateExample 8

RuCl₂ (p-cymene) dimer (100 mg, 0.1634 mmol) and ammonium formate (47mg, 0.6863, 4 equivalents) were mixed in anhydrous dichloromethane (10mL). The resulting mixture was allowed to stir at room temperature atovernight (˜16 hrs). The reaction mixture was then concentrated underreduced pressure to ˜5 mL and then hexane was added. The precipitate wasfiltered and washed with ether, dried (reduced pressure) to afford theproduct. The reaction was done under normal reflux and no inertatmosphere was created.

Example 9

RuCl₂ (p-cymene) dimer (100 mg, 0.1634 mmol) and sodium formate (47 mg,0.6863, 4 equivalent) were mixed in a round bottom flask with anhydrousdichloromethane (10 mL). The resulting mixture was allowed to stir atroom temperature overnight (˜20 hrs). The resulting red solution wasconcentrated to approximately half the volume and then hexanes wereslowly added. The mixture was cooled in ice bath to maximizeprecipitation. The solids were filtered, washed with ethyl acetate (˜5mL), dried via concentration under reduced pressure to afford 115 mg ofthis product. The reaction was done under normal reflux and no inertatmosphere was created. This product was used as such for coupling step(example 10) without further purification.

Example 10

A mixture of 2 phenylpyridine (134 mg, 0.86 mmol), 4-bromotoluene (530mg, 3 mmol), the ruthenium catalyst product of Example-9 (54 mg) andK₂CO₃ (230 mg, 1.66 mmol) in water (distilled) was heated at reflux. Theoil bath was maintained between 110° C.-120° C. The next day TLCanalysis with co-TLC of expected products indicated ˜95% conversion andthe starting material (phenyl pyridine) was present as a light spot.

The dark black reaction mixture was worked up by adding 25 mL of ethylacetate and 12 mL of water and shaking in a separating funnel to ensuremaximum extraction. The ethyl acetate layer was further washed withdeionized water. 10 mL of the ethyl acetate layer was passed through asmall plug of silica (120 mg) to remove solid particles and washedfurther with ethyl acetate. No attempt was made to separate the mixtureof mono and diarylated products and this sample was subjected to GCMSand NMR analysis as such. Based on NMR of the crude product, the ratioof mono- versus di-arylated product was established to be 1.3:0.70. GCTpremier was used to record GC MS. Analysis: retention time and retentionindex on Total Ion Chromatogram (TIC) confirmed that the product was amixture of di and mono product with minor amounts of staring material(phenyl pyridine). Peak at 13.27 minutes corresponded to the di-arylatedproduct (mass 334.2) while a peak at 9.73 minutes corresponded to themono-arylated product (244.1). An authentic sample of phenyl pyridineand arylated products was used to confirm the identity of both phenylpyridine and mono and di arylated products. The remainder of the ethylacetate layer was passed through small amounts of celite and washed withwater or filtered directly through a filter paper; crude yield from allfractions was 171 mg.

The ruthenium catalyst of Example 9 used in Example 10 had been prepared30 days earlier and kept at room temperature (no inert atmosphere). Thereaction was done under normal reflux and there was no need to create aninert atmosphere indicating the stability of the complex of Example 9.This result demonstrates an advantage of the isolated ruthenium catalystof the invention in terms of storage stability and potential use withoutspecial handling conditions (i.e., inert atmosphere).

It will be apparent, however, to one skilled in the art that thereseveral different ways to work up the experiments based on the need andrequirements.

Those of skill in the art will appreciate that embodiments not expresslyillustrated herein may be practiced within the scope of the presentdiscovery, including that features described herein for differentembodiments may be combined with each other and/or with currently-knownor future-developed technologies while remaining within the scope of theclaims presented here. It is therefore intended that the foregoingdetailed description be regarded as illustrative rather than limiting.Furthermore, the advantages described above are not necessarily the onlyadvantages of the discovery, and it is not necessarily expected that allof the described advantages will be achieved with every embodiment ofthe discovery.

What is claimed is:
 1. A ruthenium catalyst prepared by reacting onepart of [RuCl₂(p-cymene)]₂ with our parts of sodium formate indichloromethane to produce a ruthenium catalyst product; precipitatingor crystallizing the ruthenium catalyst product with hexanes; andwashing the ruthenium catalyst product with ethyl acetate.
 2. Theruthenium catalyst of claim 1, wherein the ruthenium catalyst product iscapable of catalyzing the process of preparing a biaryl compound fromfirst and second aryl compounds.